The present invention relates to an improved, Eco friendly process for the preparation of 2-[(diphenylmethyl)thio]acetamide (I), a key intermediate for the manufacturing of Modafinil.
Modafinil is a CNS stimulant and is marketed under the trade name of “Provigil”, for the treatment of narcolepsia. Lafon introduced Modafinil.
The preparation and pharmacological properties of Modafinil have been described in U.S. Pat. No. 4,177,290. U.S. Pat. No. 4,177,290 teaches two schemes (herein referred to as scheme 1 and scheme 2) for preparing Modafinil.
In scheme 1,2-[(diphenylmethyl)thio]acetic acid (III) is used as the starting material.

2-[(Diphenylmethyl)thio]acetic acid (III), on reaction with thionyl chloride yielded the corresponding 2-[(diphenylmethyl)thio]acetylchloride (IV), which on reaction with ammonia produced 2-[(diphenylmethyl)thio]acetamide (I) which on oxidation with hydrogen peroxide resulted in modafinil (II).

The aforesaid steps involve purification/separation of products in every step and the steps are not carried out in situ. In this scheme the yield of 2-[(diphenylmethyl)thio]acetamide (I) is stated to be 86% and that of Modafinil (II) as 73%.
Scheme 2 describes an industrial method for the preparation of Modafinil (II) wherein the all the reaction steps may be carried out in situ. In this scheme, the starting material is diphenylmethanol which is reacted with thiourea in the presence of HBr followed by basic hydrolysis and reaction with chloroacetic acid to form compound III. Hydrogen peroxide is then passed through the reaction mixture followed by acidification with hydrochloric acid to form (benzhydrylsulfinyl)acetic acid. The acid is reacted with dimethyl sulphate in presence of soda lye and sodium bicarbonate to obtain methyl(benzhydrylsulfinyl)acetate. After filtration methyl(benzhydrylsulfinyl)acetate is dissolved in methanol and ammonia is bubbled through the reaction mixture. After recrystallization and drying of the reaction mass Modafinil (II) is obtained with 41% total yield calculated from benzhydrol. The in-situ reaction scheme 2 is set out below.

The synthetic methods described in U.S. Pat. No. 4,177,290 have some inherent drawbacks. In scheme 1, the preparation of Modafinil involves three chemical steps with the yield in the final step being 73% and cumulative yield of Modafinil being 63%. The scheme does not involve reactions in-situ and require purification of products at the end of each step. Furthermore, thionyl chloride has been used for converting compound III to its acid chloride. Thionyl chloride is corrosive, hazardous, environmentally unfriendly and difficult to handle at commercial scale. Thus, the disclosed scheme is not suitable for industrial use. Moreover during the reaction, SO2 and HCl are evolved as biproduct. To scrub out these gases, extra infrastructure is required. In addition to this, any leakage of these gases will lead to air pollution, which is injurious to the person living around and working in the plant.
With regard to scheme 2, the industrial method described therein gives very low yield of 41%. Moreover, the esterification of the sulphinyl acetic acid is carried out using dimethyl sulfate which is a well known hazardous reagent.
Thus there is a need for an improved process for the preparation of Modafinil to get higher yield-without the use of hazardous reagents.